Tirasemtiv

Tirasemtiv is an activator of the fast skeletal troponin complex.¹ It selectively binds to purified fast skeletal troponin complex (K_d = 40 nM) over slow skeletal (K_d = 3,800 nM) and cardiac troponin complexes. Tirasemtiv (20 μM) slows the rate of calcium release from the fast skeletal troponin complex. It increases the ATPase activity of isolated rabbit fast skeletal myofibrils at a fixed calcium concentration (EC₅₀ = 390 nM) and sensitizes skinned fast skeletal muscle fibers isolated from human and rabbit to calcium in a concentration-dependent manner. Tirasemtiv increases in situ extensor digitorum longus (EDL) muscle force and forelimb grip strength in a rat model of myasthenia gravis. It also increases forelimb grip strength, grid hang test performance, and rotarod performance in a mouse model of amyotrophic lateral sclerosis (ALS) when administered at a dose of 10 mg/kg.²

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1. Russell, A.J., Hartman, J.J., Hinken, A.C., et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med. 18(3), 452-455 (2012).

2. Hwee, D.T., Kennedy, A., Ryans, J., et al. Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. PLoS One 9(5), e96921 (2014).